Type I diabetes mellitus (T1DM) is a T cell-mediated autoimmune disease of the pancreas resulting from the destruction of insulin-producing beta cells. The timing and the magnitude of the autoimmune response can be modulated by a number of genetic and environmental factors. The non-obese diabetic (NOD) mouse serves as an excellent model for the autoimmune component of human T1 DM. In this model, the disease is driven by diabetogenic (autoimmune) T cells. The complex regulation of these T cells is poorly understood in mouse and man. Evidence indicates that the TH1 (interferon gamma (IFNgamma-producing) T cells are important in protection and exasperation of the disease. Therefore this cytokine is central to the autoimmune response. This proposal will study the mechanism of regulatory cell protection of the onset of diabetes in the NOD murine model of disease with a special interest in the activity of IFNgamma. Knowledge about the mechanisms of disease control is vital for the discovery of a cure or better methods of treatment. The hypothesis to be studied is that the production of IFNgamma by regulatory cells and the balance between regulatory and diabetogenic T cells in the pancreas control disease progression. This hypothesis will be tested in the following specific aims. Aim 1. To determine the effector function and cell fate of diabetogenic T cells under in vivo regulation by IFNgamma-deficient and competent NOD T cells. AIM 2. To determine the mechanism by which IFN-gamma modulates the diabetogenic potential of BDC2.5 T cells in vivo. Cincinnati Children's Hospital Research Foundation has established an enviable reputation in biomedical research and this is reflected in the excellent environment of reputable scientists, laboratory space, sponsoring of guest lecturers and courses that enhance new ideas and methodology. These activities are furthered facilitated by a number of core facilities including an excellent animal facility. The candidate's career goals are to combine a background in immunology with the study of diabetes in order to become an independent investigator. The career development plan is to become proficient in the technique of functional genomics to expand the candidate's knowledge in this important area.